Primary Hyperparathyroidism is described best today as a relatively asymptomatic disease characterized by mild elevations in the serum calcium and parathyroid hormone concentrations. Over the past 18 years, this research project has helped to define the clinical, biochemical, densitometric and histomorphometric features of primary hyperparathyroidism in the modern era. As a major source of new insights, the investigation has helped to elucidate aspects of this disease that were not previously appreciated. The overall objective of this research project remains the definitive description of extent, course, and reversibility of the manifestations of primary hyperparathyroidism. Other important challenges will be pursued in order to achieve a more complete understanding of primary hyperparathyroidism. The following Specific Aims will be pursued: (1) to define the natural history of primary hyperparathyroidism, and the reversibility of its manifestations, over a uniquely long, systematic 23-year period of investigation. This effort will include characterization of new areas of inquiry in neuropsychological function, histomorphometric, geometrical, and cellular aspects of bone in primary hyperparathyroidism; (2) to characterize a newly recognized presentation of asymptomatic primary hyperparathyroidism without hypercalcemia; (3) to complete the characterization of the bone remodeling unit in primary hyperparathyroidism; 4) to determine fracture risk in primary hyperparathyroidium. This project will utilize state-of-the-art techniques, including bone densitometry, peripheral quantitative tomography, bone histomorphometry, quantitative backscattered electron imaging, quantitative assessment of vertebral fractures, and cognitive assessment. By the end of the renewal period, we expect to have fully characterized the long-term natural history of hyperparathyroidism, with or without surgery, as well has to have defined features of this disease that have, up to now, eluded successful investigation. The results should lead to the establishment of rational recommendations for the management of primary hyperparathyroidism.